Condensed benzopyrone derivatives

ABSTRACT

The present invention relates to new condensed benzopyrone derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds having the following general formula(I) ##STR1## wherein n is 1 or 2;

R₁ is

(a) hydrogen, halogen or C₁ -C₆ alkyl;

(b) cyano, aminocarbonyl, 5-tetrazolyl, carboxy or a C₁ -C₆alkoxycarbonyl group unsubstituted or substituted by a di(C₁-C₆)alkylamino group;

(c) nitro, amino, morpholino, piperidino or N- pyrrolidinyl;

(d) a ##STR2## group, wherein R₃ is hydrogen or C₁ -C₆ alkyl and R₄ is:

(a') formyl, C₂ -C₆ alkanoyl or C₁ -C₆ alkyl, wherein the alkyl isunsubstituted or substituted by one or two substituents chosen fromhydroxy and phenyl;

(b') a --(CO)_(m) --A--R₅ group, wherein m is zero or 1; A completes asingle bond, or is a phenylene moiety, or it is a branched or straightC₁ -C₆ alkylene or C₂ -C₆ alkenylene chain and R₅ is:

(a") carboxy or C₁ -C₆ alkoxycarbonyl, unsubstituted or substituted by adi-(C₁ -C₆)alkyl-amino group; or

(b") halomethyl or ##STR3## wherein each of R₆ and R₇ is independentlyhydrogen or C₁ -C₆ alkyl or R₆ and R₇, taken together with the nitrogenatom to which they are linked, form a heterocyclic ring chosen fromN-pyrrolidinyl, N-piperazinyl, piperidino and morpholino, wherein theN-piperazinyl ring is unsubstituted or substituted by C₁ -C₆ alkyl,phenyl or by pyridyl, the piperidino ring is unsubstituted orsubstituted by one or two C₁ -C₆ alkyl groups, and the morpholino ringis unsubstituted or substituted by methyl;

(e) hydroxy or a --OR₄ group, wherein R₄ is as defined above;

R₂ represents a thienyl, a furyl or a pyridyl group, wherein each ofthese groups is unsubstituted or substituted by a C₁ -C₃ alkyl group, orR₂ is a group of formula ##STR4## wherein each of R₈, R₉ and R₁₀ isindependently hydrogen; halogen; C₁ -C₆ alkyl; hydroxy; C₁ -C₆ alkoxy;C₃ -C₄ alkenyloxy; formyloxy; C₂ -C₆ alkanoyloxy; carboxy; C₁ -C₆alkoxycarbonyl; nitro; or a group ##STR5## wherein each of R₁₁ and R₁₂independently represents hydrogen, C₁ -C₆ alkyl, formyl or C₂ -C₆alkanoyl; or any two adjacent R₈, R₉ and R₁₀ groups, taken together,form a C₁ -C₃ alkylenedioxy group, and the pharmaceutically acceptablesalts thereof, and wherein, when n is 1 and, at the same time, R₂ isunsubstituted phenyl, R₁ is other then hydrogen.

The scope of this invention includes also all the possible isomers ofthe compounds of formula (I) (e.g. Z and E isomers and optical isomers)and the mixture thereof. The numbering used to identify the position ofthe substituents in the compounds of formula (I) is the following one:##STR6## R₁ may be on the C₅ or C₆ or C₇ or C₈ carbon atom, preferablyit is on the C₆ or C₇ carbon atom.

The alkyl, alkylene, alkenylene, alkylamino, alkoxycarbonyl, alkoxy,alkenyloxy, alkanoyl and alkanoyloxy groups may be branched or straightchain groups.

A C₁ -C₆ alkyl group is preferably a C₁ -C₄ alkyl group, in particularmethyl, ethyl, propyl and isopropyl.

A halogen atom is, for example, fluorine, chlorine and bromine,preferably it is fluorine and chlorine.

A halomethyl group is preferably chloromethyl and bromomethyl.

A C₁ -C₆ alkoxycarbonyl group, is preferably a C₁ -C₄ alkoxycarbonylgroup, in particular, methoxycarbonyl and ethoxycarbonyl.

A C₂ -C₆ alkanoyl group is, for example, acetyl, propionyl, butyryl,valeryl and isovaleryl, preferably acetyl.

A C₁ -C₆ alkoxy group is for example a C₁ -C₄ alkoxy group, inparticular methoxy and ethoxy.

A C₁ -C₃ alkylenedioxy group is for example methylenedioxy andethylenedioxy.

A branched or straight C₁ -C₆ alkylene chain is, preferably, a branchedor straight C₁ -C₄ alkylene chain, in particular, for example, ##STR7##

A branched or straight C₂ -C₆ alkenylene chain is, preferably, abranched or straight C₂ -C₄ alkenylene chain, in particular, forexample, ##STR8##

A C₂ -C₆ alkanoyloxy group is, for example, acetoxy, propionyloxy andbutyryloxy, preferably is acetoxy.

When one or more of R₃, R₄, R₆, R₇, R₁₁ and R₁₂ is a C₁ -C₆ alkylgroups, the alkyl group is preferably a C₁ -C₄ alkyl group, inparticular methyl, ethyl, propyl and isopropyl. When one or more of R₈,R₉ and R₁₀ is a C₁ -C₆ alkyl group, the alkyl group is preferablymethyl, ethyl, propyl or butyl.

When one or more of R₈, R₉ and R₁₀ is a C₁ -C₆ alkoxy group, the alkoxygroup is preferably methoxy, ethoxy, propoxy, isopropoxy and butoxy.

When R₆ and R₇, taken together with the nitrogen atom to which they arelinked, form an heterocyclic ring as defined above, it is preferablychosen from N-pirrolidinyl, N-piperazinyl unsubstituted or substitutedby C₁ -C₃ alkyl and morpholino unsubstituted or substituted by methyl.

Preferred compounds of the invention are the compounds of formula (I),wherein

n is 1 or 2;

R₁ is carboxy or 2-[di-(C₁ -C₂)alkylamino]-ethoxy-carbonyl;5-tetrazolyl; amino, hydroxy or C₁ -C₂ alkoxy-carbonylamino; methyl; agroup --NHR₁₃ or --OR₁₃, wherein R₁₃ is (a"') --COCOOH or--CO--CH═CH--COOH,(b"') --CO--A'--R₁₄, wherein A' is a phenylene groupor a --(CH₂)_(p) --moiety, wherein p is 1, 2 or 3 and R₁₄ is carboxy ora group ##STR9## wherein R₆ and R₇ are as defined above, or R₁₃ is (c"')a group --(CH₂)_(q) --COOH wherein q is 1, 2 or 3;

R₂ is thienyl or pyridyl, wherein the thienyl and the pyridyl areunsubstituted or substituted by a C₁ -C₃ alkyl group or R₂ is a group##STR10## wherein each of R₈, R₉ and R₁₀ is independently hydrogen,fluorine, chlorine, C₁ -C₂ alkyl, hydroxy, C₁ -C₃ alkoxy, acetoxy,carboxy, amino, di-(C₁ -C₂)alkylamino, or any two adjacent R₈, R₉ andR₁₀ groups, taken together form a methylenedioxy group; and thepharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula(I), wherein

n is 1 or 2;

R₁ is carboxy or 2-[di-(C₁ -C₂)alkylamino]-ethoxy-carbonyl;5-tetrazolyl; amino, hydroxy or C₁ -C₂ alkoxy-carbonylamino; methyl; agroup --NHR₁₃ or --OR₁₃, wherein R₁₃ is (a"') --COCOOH or--CO--CH═CH--COOH, (b"') --CO--(CH₂)_(p) --R₁₄, wherein p is 1 or 2 andR₁₄ is carboxy or a group ##STR11## wherein each of R₆ and R₇ isindependently hydrogen or C₁ -C₄ alkyl or R₆ and R₇, taken together withthe nitrogen atom to which they are linked, form a N-piperazinyl ringunsubstituted or substituted by C₁ -C₃ alkyl, or a morpholino ringunsubstituted or substituted by methyl; or R₁₃ is (c"') a group--(CH₂)_(q) --COOH, wherein q is 1 or 2;

R₂ is thienyl or pyridyl, wherein the thienyl and the pyridyl areunsubstituted or substituted by a methyl group or R₂ is a group##STR12## wherein each of R₈, R₉ and R₁₀ is independently hydrogen,fluorine, chlorine, C₁ -C₂ alkyl, hydroxy, C₁ -C₃ alkoxy, acetoxy,carboxy, amino, di-(C₁ -C₂)alkylamino, or any two adjacent R₈, R₉ andR₁₀ groups, taken together form a methylenedioxy group; and thepharmaceutically acceptable salts thereof.

Examples of pharmaceutically acceptable salts are either those withinorganic bases, such as sodium, potassium, calcium and aluminiumhydroxides or with organic bases, such as lysine, triethylamine,triethanolamine, dibenzylamine, methylbenzylamine,tris-(hydroxymethyl)-aminomethane, piperidine, N-ethylpiperidine,N,N-diethylaminoethylamine, N-ethylmorpholine, β-phenethylamine,N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamine and the otheracceptable organic amines, as well as the salts with inorganic acids,e.g. hydrochloric, hydrobromic, nitric and sulphuric acids and withorganic acids, e.g. citric, tartaric maleic, malic, fumaric,methanesulphonic and ethanesulphonic acids.

Examples of particularly preferred compounds of the invention are:

4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid;

4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-benzylidene-6-N-(2-morpholino-ethyl)-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-oxaceticacid;

N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxaceticacid;

N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-aceticacid;

(E)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid;

(Z)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid;

and the pharmaceutically acceptable salts thereof, in particular thesodium, triethanolamine and tris-(hydroxy-methyl)-aminomethane salts andthe hydrochlorides, and the basic esters (e.g. those with2-diethylamino-ethanol) and the C₁ -C₆ alkyl esters thereof, inparticular the methyl, ethyl, isopropyl and n-butyl esters.

The compounds of formula (I) may be obtained by a process comprising

(a) reacting a compound of formula (II) ##STR13## wherein n and R₁ areas defined above or a salt thereof, with an aldehyde of formula (III)##STR14## wherein R₂ is as defined above; or

(b) dehydrating a compound of formula (IV) ##STR15## wherein n, R₁ andR₂ are as defined above; and if desired, converting a compound offormula (I) into another compound of formula (I) and/or, if desired,converting a compound of formula (I) into a pharmaceutically acceptablesalt thereof and/or, if desired, converting a salt into a free compoundand/or, if desired, separating a mixture of isomers into the singleisomers.

Preferred salts of a compound of formula (II) are those with inorganicbases such as the sodium or potassium salts as well as the salts withinorganic acids e.g. hydrochloric, hydrobromic, hydroiodic and sulphuricacid. The reaction of a compound of formula (II) with an aldehyde offormula (III) may be carried out, for example, in the presence of basiccondensing agents, for example, sodium ethoxide, sodium methoxide,potassium tert.butoxide, sodium hydride, sodium amide, in a solvent,preferably selected from the group consisting of methanol, ethanol,dioxane, dimethylformamide and their mixtures, at a temperature rangingbetween 0° C. and about 100° C.

During the reaction of a compound of formula (II) with a compound offormula (III) the intermediate compounds of formula (IV) are formed,which usually are not isolated because spontaneously dehydrate to givethe corresponding compounds of formula (I): only in a few cases,depending on the nature of the aldehyde (III) and on the experimentalconditions (e.g., reaction temperature ranging from 0° C. to about roomtemperature), the compounds of formula (IV) can be isolated and furtherprocessed to give the compounds of formula (I).

The dehydration of a compound of formula (IV) may be carried out, forexample, by acid catalysis, by heating the compound in a solvent such asmethanol, ethanol, dioxane or acetic acid in the presence of an acidsuch as HCl, HBr, Hl, H₂ SO₄, p-toluenesulphonic or methanesulphonicacid, at a temperature ranging from about 50° C. to the refluxtemperature.

Alternatively the dehydration of a compound of formula (IV) may becarried out by basic catalysis by heating the compound in a solvent suchas methanol, ethanol or dioxane, in the presence of a base such as NaOH,KOH, K₂ CO₃, Na₂ CO₃, NaOCH₃, NaOC₂ H₅, at a temperature ranging fromabout 50° C. to the reflux temperature.

A compound of formula (I) may be converted, as stated above, intoanother compound of formula (I) by known methods; for example, acompound of formula (I) wherein R₁ is a C₁ -C₆ alkoxycarbonyl group maybe converted into a compound of formula (I), wherein R₁ is a freecarboxy group, by hydrolysis, e.g. basic hydrolysis, using, for example,sodium or potassium hydroxide, in a solvent, such as water, dioxane,dimethylformamide or a lower aliphatic alcohol and their mixtures, andoperating at a temperature ranging from the room temperature to about100° C.; the same reaction may be also carried out e.g. by treatmentwith lithium bromide in dimethylformamide at a temperature higher than50° C. or by treatment with hydrochloric or hydrobromic or hydroiodic orsulphuric acid in acetic acid at temperature higher than 50° C.

A compound of formula (I) wherein R₁ is a free carboxy group may beconverted into a compound of formula (I) wherein R₁ is a C₁ -C₆alkoxycarbonyl group unsubstituted or substituted by a di-(C₁-C₆)alkyl-amino group by converting the carboxylic acid into thecorresponding halocarbonyl, preferably chlorocarbonyl, derivative, byreaction, e.g. with the desired acid halide, for example oxalylchloride, thionyl chloride, PCl₃, PCl₅ or POCl₃, either in the absenceof solvents or in an inert organic solvent such as benzene, toluene,xylene, dioxane, dichloroethane, methylene chloride or tetrahydrofuran,at a temperature ranging preferably from about 0° C. to about 120° C.,and then reacting the resulting halocarbonyl derivative with a suitableC₁ -C₆ alkyl alcohol, unsubstituted or substituted by a di-(C₁-C₆)alkyl-amino group, in an inert solvent such as benzene, toluene,xylene, dioxane, dichloroethane, methylene chloride or tetrahydrofuran,at temperature varying between about 0° C. and about 120° C., preferablyin the presence of a base such as triethylamine or pyridine.

Alternatively the esterification of a free carboxy group in a compoundof formula (I) may be effected, for example, by reacting the acid with asuitable optionally substituted C₁ -C₆ alkyl alcohol in the presence ofa Lewis acid such as gaseous hydrochloric acid, 98% sulphuric acid,boron trifluoride etherate at a temperature varying from roomtemperature and the reflux temperature.

Furthermore, for example, a compound of formula (I) wherein R₁ is a freeamino group may be converted into a compound of formula (I) wherein R₁is a group --NHCO--A--COOH, wherein A is as defined above, except asingle bond, by reaction with a compound of formula ##STR16## wherein Ais as defined above, except a single bond, in an inert solvent such asdichloromethane, dichloroethane, chloroform, tetrahydrofuran,dimethylformamide, dimethylacetamide, at a temperature varying betweenroom temperature and about 100° C.

Alternatively, for example, a compound of formula (I) wherein R₁ is agroup of formula --NHCO--A--COOH, wherein A is as defined above, may beobtained by reacting a compound of formula (I) wherein R₁ is a freeamino group with a compound of formula ZCO--A--R'₅, wherein A is asdefined above, Z is halogen, preferably chlorine, and R'₅ is a C₁ -C₆alkoxycarbonyl group, under the same experimental conditions as definedabove for the reaction of a compound of formula (I) with a compound offormula (V), so to obtain a compound of formula (I) wherein R₁ is agroup --NHCO--A--R'₅, wherein A and R'₅ are as defined above, whichcompound is in turn converted into a compound of formula (I) wherein R₁is a group --NHCO--A--COOH, wherein A is as defined above, for example,by basic hydrolysis, using aqueous NaOH or KOH in a solvent such asdioxane, dimethylformamide, dimethylacetamide at a temperature varyingfrom 0° C. to about 50° C.

Furthermore, a compound of formula (I) wherein R₁ is a group--NH--(CO)_(m) --A--R"₅, wherein m and A are as defined above and R"₅ ishalomethyl may be converted into a compound of formula (I) wherein R₁ isa group ##STR17## wherein m, A, R₆ and R₇ are as defined above, forexample, by reaction with a compound of formula ##STR18## wherein R₆ andR₇ are as defined above, in an inert organic solvent such as dioxane,dimethylformamide, dimethylacetamide, at a temperature varying betweenthe room temperature and the reflux temperature, preferably between theroom temperature and about 100° C. Furthermore, for example, a compoundof formula (I) wherein R₁ is a group ##STR19## wherein R₄ is as definedabove, may be converted into a compound of formula (I) wherein R₁ is agroup ##STR20## wherein R₄ is as defined above and R'₃ is C₁ -C₆ alkyl,by reacting with a suitable C₁ -C₆ alkyl halide in the presence of abase such as Na₂ CO₃, K₂ CO₃, NaH, NaNH₂, in a solvent such asdimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran and theirmixtures, at a temperature varying between room temperature and about100° C.

Furthermore, for example, a compound of formula (I) wherein R₁ is aformylamino or a C₂ -C₆ alkanoylamino group, may be converted into acompound of formula (I) wherein R₁ is a free amino group by acidhydrolysis using, for example, hydrochloric, hydrobromic or hydroiodicacid in aqueous solution in the presence, if necessary, of an organiccosolvent such as dioxane or acetic acid, operating at a temperaturevarying between room temperature and reflux temperature.

Furthermore, for example, a nitro group may be converted into an aminogroup by treatment, for example, with stannous chloride in concentratedhydrochloric acid, using, if necessary, an organic cosolvent such asacetic acid, dioxane, tetrahydrofuran, at a temperature ranging betweenroom temperature and about 100° C.

Furthermore, for example, a free hydroxy or amino group, may beconverted respectively into a C₂ -C₆ alkanoyloxy or C₂ -C₆ alkanoylaminogroup using conventional methods well known in organic chemistry.

Furthermore, for example, a compound of formula (I), wherein R₁ iscarboxy, may be converted into a compound of formula (I), wherein R₁ is5-tetrazolyl by known methods, for example, by converting the carboxygroup into the corresponding halide, preferably the chloride, byreaction, e.g., with thionyl chloride in benzene or dioxane ordichloroethane, at a temperature ranging from the room temperature toabout 100° C., then by reacting the halide with ammonia, at roomtemperature in one of the above mentioned solvents, to give thecorresponding amide and by dehydrating the amide to give the nitrile,e.g., by means of p-toluenesulphonyl chloride in pyridine anddimethylformamide, at a temperature ranging from about 30° C. to about100° C., and finally reacting the nitrile with sodium azide and ammoniumchloride in dimethylformamide at a temperature ranging from the roomtemperature to about 100° C.

Also the optional salification of a compound of formula (I) as well asthe conversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods.

For example the separation of a mixture of optical isomers into theindividual isomers may be carried out by salification with an opticallyactive base or with an optically active acid and subsequent fractionalcrystallization.

Thus, the separation of a mixture of geometric isomers may be carriedout, for example, by fractional crystallization.

The compounds of formula (II) may be prepared, for example by reacting acompound of formula (VI) ##STR21## wherein R₁ is as defined above, R₁₅is halogen, preferably chlorine and bromine, or a group --OCOOR₁₇,wherein R₁₇ is C₁ -C₆ alkyl, phenyl or benzyl, and R₁₆ is a C₁ -C₁₀ acylradical, preferably a C₁ -C₆ alkanoyl radical, in particular acetyl,with a compound of formula (VII) ##STR22## wherein n is as defined aboveand each of R₁₈ and R₁₉ is independently C₁ -C₆ alkyl or R₁₈ and R₁₉,taken together with the nitrogen atom to which then are linked, form aN-pyrrolidinyl, a morpholino or a piperidino radical, wherein thepiperidino ring is unsubstituted or substituted by one or two methylgroups.

The reaction between a compound of formula (VI) and a compound offormula (VII) may be carried out, for example, in an inert solvent suchas benzene, toluene, chloroform, dichloromethane, dichloroethane,dioxane, at a temperature varying between about 0° C. and about 50° C.so as to obtain an intermediate compound, having presumably the formula(VIII) ##STR23## wherein n, R₁, R₁₈ and R₁₉ are as defined above; thecompound of formula (VIII), which is not usually isolated from thereaction mixture, is in turn converted into a compound of formula (II),e.g. by heating with aqueous organic basis, such as pyridine orpiperidine.

The compounds of formula (III), (VI) and (VII) are known compounds ormay be prepared by conventional methods: in some cases they arecommercially available products. The compounds of the invention areuseful for the prevention and the treatment of all the diseases in whichanaphylactic mediators are involved, for example, the allergicaffections.

Therefore the compounds of the invention are useful in the preventionand treatment, e.g., of allergic rhinitis, hay fever, urticaria,dermatitis and, in particular they are effective in the prevention andtreatment of the allergic bronchial asthma.

The activity of the compounds of the invention is shown, e.g., by thefact that they are active in the following biological tests:

in vitro

(1) test of A 23187 induced SRS production from rat peritoneal cells,according to M. K. Bach and J. R. Brashler (J. Immunol., 113, 2040,1974);

(2) test of antigen induced SRS production from guinea-pig chopped lung,according to W. E. Brochlehurst (J. Physiol., 151, 416, 1960);

in vivo

(3) test of the IgE mediated passive cutaneous anaphylaxis (PCA) in therat, according to A. M. J. N. Blair (Immunology, 16, 749, 1969).

The results of these biological tests show that the compounds of theinvention are active, for example, as inhibitors of the immunologicalrelease of mediators, e.g. histamine, from the mast cells and asinhibitors of the production and/or release of anaphylactic mediatorssuch as "slow reacting substances" (SRS) in the peritoneal and thepulmonary system, induced by challenge with an ionophore or with anantigen.

As preferred example of compound having antiallergic activity thefollowing can be mentioned:

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid.

In view of their high therapeutic index the compounds of the inventioncan be safely used in medicine. For example, the approximate acutetoxicity (LD₅₀) of the compound3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid in the mouse, determined with single administration of increasingdoses and measured on the seventh day after the day of treatment is peros higher than 800 mg/kg. Analogous toxicity data have been found forthe other compounds of the invention.

The compounds of the invention may be administered in conventionalmanner, for instance, orally or parenterally at a daily dosagepreferably from about 0.5 to about 15 mg/kg, or by inhalation,preferably at a daily dosage from about 0.5 to about 100 mg, preferably0.5 to 25 mg, or by topical application, (for example for the treatmentof urticaria and dermatosis), e.g. by a cream containing about from 0.5to 5 mg, preferably 1-2 mg, of the active principle per 100 mg of cream.

The nature of the pharmaceutical compositions containing the compoundsof this invention in association with pharmaceutically acceptablecarriers or diluents will, of course, depend upon the desired route ofadministration. The compositions may be formulated in the conventionalways with the usual ingredients. For example, the compounds of theinvention may be administered in the form of aqueous or oily solutionsor suspensions, aerosols, as well as powders, tablets, pills, gelatinecapsules, syrups, drops, suppositories, or creams, or lotions fortopical use.

Thus, for oral administration, the pharmaceutical compositionscontaining the compouns of this invention, are preferably tablets, pillsor gelatine capsules which contain the active substance together withdiluents, such as lactose, dextrose, sucrose, mannitol, sorbitol,cellulose; lubricants, for instance, silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; or they mayalso contain binders, such as starches, gelatine, methylcellulose,carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone;disaggregating agents, such as starches, alginic acid, alginates, sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polisorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations.

Said pharmaceutical preparations may be manufactured in known manner,for example, by means of mixing, granulating, tabletting, sugar-coating,or film-coating processes. For the treatment of allergic asthma, thecompounds of the invention are also administered by inhalation. For suchuse, suitable compositions may comprise a suspension or solution of theactive ingredient, preferably in the form of a salt, such as the sodiumsalt or the salt with triethanolamine or withtris-(hydroxymethyl)-aminomethane, in water, for administration by meansof a conventional nebulizer.

Alternatively, the compositions may comprise a suspension or a solutionof the active ingredient in a conventional liquified propellant, such asdichlorodifluoromethane or dichlorotetrafluoroethane to be administeredfrom a pressurized container, i.e., an aerosol dispenser. When themedicament is not soluble in the propellant, it may be necessary to adda co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate,and/or surface-active agent to the composition, in order to suspend themedicament in the propellant medium and such surface-active agents maybe any of those commonly used for this purpose, such as non-ionicsurface-active agents, e.g., lecithin.

The compounds of the invention may also be administered in the form ofpowders by means of a suitable insufflator device and in this case thefine particle sized powders of the active ingredients may be mixed witha diluent material such a lactose.

Furthermore, the compounds of this invention may also be administered byintradermal or intravenous injection in the conventional manner.

In addition to the internal administration, the compounds of thisinvention may find use in compositions for topical application, e.g. ascreams lotions or pastes for use in dermatological treatments.

For these compositions the active ingredient may be mixed withconventional oleaginous or emulsifying excipients. The followingexamples illustrate but do not limit the present invention.

EXAMPLE 1

1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid,methyl ester, m.p. 156°-158° C. (5.1 g) was reacted with 2-methylbenzaldehyde (3.3 g) in methanol (80 ml) in the presence of sodiummethylate (2.28 g) under stirring at room temperature for 20 hours. Theprecipitate was filtered and washed with methanol and then with wateruntil neutral: crystallization from CH₂ Cl₂ -methanol gave 5.2 g of3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 203°-205° C.

By proceeding analogously the following compounds were prepared:

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 216°-218° C.;

3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 202°-204° C.;

3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 205°-207° C.;

3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 209°-211° C.;

3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 181°-183° C.;

3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 204°-207° C.;

3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 251°-253° C.;

3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 193°-195° C.;

3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 219°-222° C.;

3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 217°-220° C.;

3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 208°-211° C.;

3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 189°-192° C.;

3-(2,4-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 212°-214° C.;

3-(2,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 260°-264° C.;

3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 210°-213° C.;

3-(3,4-methylenedioxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 270°-272° C.;

3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2-ethoxy-3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2,3,4-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 221°-224° C.;

3-(4-N,N-dimethylamino-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 224°-226° C.;

3-(4-hydroxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(4-nitro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2-propoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3-propoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(4-propoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(3-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(4-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 168°-170° C.;

3-(3,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 237°-240° C.;

3-(2,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 255°-258° C.;

3-(2-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester; and

3-(3-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester.

EXAMPLE 2

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester (3 g) was hydrolized by treatment with 1% KOH in 95%ethanol (59 ml) at reflux temperature for 15 minutes. After cooling,acidification with HCl and dilution with ice water, the precipitate wasfiltered and washed with water. Crystallization fromdimethylformamide-ethanol gave 2.4 g of3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 296°-298° C., NMR (CF₃ COOD) δppm: 2.59 (s) (3H, --CH₃), 3.40(bs) (4H, C-1 and C-2 protons), 7.38-7.87 (m) (4H, phenyl protons), 8.10(d) (1H, C-5 proton), 8.30 (bs) (1H, ═CH--), 8.80 (dd) (1H, C-6 proton),9.30 (d) (1H, C-8 proton).

By proceeding analogously the following compounds were prepared:

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 344°-347° C.;

3-(3-methyl-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 309°-310° C.;

3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 340°-342° C.;

3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 291°-295° C.;

3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 288°-290° C.;

3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 320°-321° C.;

3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 313°-314° C.;

3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 320°-322° C.;

3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 362°-363° C.;

3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 263°-264° C.;

3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 349°-350° C.;

3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 321°-324° C.;

3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 300°-302° C.;

3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 297°-299° C.;

3-(2,4-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 329°-331° C.;

3-(2,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 318°-319° C.;

3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 336°-337° C.;

3-(3,4-methylenedioxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 343°-345° C.;

3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 308°-310° C.;

3-(2-ethoxy-3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,3,4-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 311°-313° C.;

3-(4-N,N-dimethylamino-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 350°-353° C.;

3-(2-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-hydroxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-nitro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-propoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3-propoxy-benzylidene)-1,2,3-9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-propoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(3-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(4-isopropoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 290°-292° C.;

3-(3,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 353°-356° C.; and

3-(2,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 340°-343° C.

EXAMPLE 3

1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid,methyl ester (3 g) was reacted with 6-methyl-2-pyridinecarboxaldehyde(1.95 g) in methanol (60 ml) in the presence of sodium methylate (1.35g) under stirring at room temperature for 8 hours. The precipitate wasfiltered and washed with methanol and then with water until neutral.Purification over SiO₂ column using chloroform as eluent allowed toseparate two components of the crude product of the reaction, both ofwhich were crystallized from chloroform-isopropyl ether: 0.7 g of3-[(6-methyl-2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 200°-202° C. and 1,4 g of3-(α-hydroxy-6-methyl-2-picolyl)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 210°-212° C.

EXAMPLE 4

3-(α-hydroxy-6-methyl-2-picolyl)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester (1 g) was heated at the reflux temperature for 24hours in methanol (30 ml) containing 37% HCl (1.5 ml).

After cooling, neutralization with NaOH and dilution with ice water, theprecipitate was filtered and crystallized from methanol to give 0.6 g of3-[(6-methyl-2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 200°-202° C., which was hydrolyzed by treatmentwith 0.5% KOH in 95% ethanol (23 ml) at the reflux temperature for 10minutes. After cooling, neutralization with HCl and dilution with icewater, the precipitate was filtered and crystallized from methanol togive 0.4 g of3-[(6-methyl-2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 250° C. dec., NMR (CDCl₃ -CF₃ COOD) δppm: 2.91 (s) (3H,--CH₃), 3.29 (bs) (4H, C-1 and C-2 protons), 7.52 (bs) (1H, ═CH--), 7.75(d) and 7.84 (d) and 8.04 (d) (3 H, C-5 proton; C-3 and C-5 pyridylprotons), 8.50 (t) (1H, C-4 pyridyl proton), 8.63 (dd) (1H, C-6 proton),9.12 (d) (1H, C-8 proton).

EXAMPLE 5

1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid,methyl ester (2 g), was reacted with 2-ethoxy-benzaldehyde (1.7 g) inmethanol (55 ml) in the presence of sodium methylate (0.9 g) understirring at room temperature for 24 hours. The precipitate, was filteredand washed with methanol and then with water until neutral: it was foundto be a mixture of the compounds3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester and3-(α-hydroxy-2-ethoxy-benzyl)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 162°-168° C.

The mixture (1.7 g), without separation of the components, was heatedwith 37% HCl (17 ml) in acetic acid (17 ml) at the reflux temperaturefor 5 hours. After cooling the precipitate was filtered, washed withwater and then crystallized from dioxane to give 1.2 g of3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 300°-302° C., NMR (CDCl₃ -CF₃ COOD) δppm: 1.51 (t) (3H,--OCH₂ CH₃), 3.17 (bs) (4H, C-1 and C-2 protons), 4.20 (q) (2H, --OCH₂CH₃), 7.04 (m) (2H, C-3 and C-5 phenyl protons), 7.41 (bt) (1H, C-4phenyl proton), 7.60 (bd) (1H, C-6 phenyl proton), 7.85 (d) (1H, C-5proton), 8.00 (bs) (1H, ═CH--), 8.50 (dd) (1H, C-6 proton), 9.03 (d)(1H, C-8 proton).

EXAMPLE 6

1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylic acid,m.p. 273°-275° C. (1.6 g) was reacted with 2-methoxy-benzaldehyde (1 g)in methanol (60 ml) in the presence of sodium methylate (1.3 g) understirring at 45° C. for 7 hours. After cooling, the reaction mixture wasacidified with 37% HCl and the precipitate was filtered and washed withmethanol and then with water until neutral. Crystallization fromchloroform-ethanol gave 1.2 g of3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 291°-295° C., NMR (CH₃ COOD) δppm: 3.36 (bs) (4H, C-1 and C-2protons), 4.09 (s) (3H, --OCH₃), 7.09-7.87 (m) (4H, phenyl protons),8.07 (d) (1H, C-5 proton), 8.41 (bs) (1H, ═CH--), 8.76 (dd) (1H, C-6proton), 9.28 (d) (1H, C-8 proton).

EXAMPLE 7

By proceeding according to Examples 1, 2, 5 and 6 using suitableheterocyclic aldehydes, the following compounds were obtained:

3-(2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 219°-222° C.;

3-(3-methyl-2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(5-methyl-2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 250°-252° C.;

3-[(4-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2-furfurylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester, m.p. 203°-205° C.;

3-(5-methyl-2-furfurylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester;

3-(2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 344°-346° C.;

3-(3-methyl-2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(5-methyl-2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 325°-328° C.;

3-[(4-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;

3-(2-furfurylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 338°-343° C.; and

3-(5-methyl-2-furfurylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid.

EXAMPLE 8

1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid, methyl ester,m.p. 140°-142° C. (2 g), was reacted with benzaldehyde (1.1 g) inmethanol (40 ml) in the presence of sodium methylate (0.75 g) understirring at 50° C. for 24 hours.

After cooling the precipitate was filtered and washed with methanol andthen with water: crystallization from CH₂ Cl₂ -methanol gave 1.3 g of4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid,methyl ester, m.p. 168°-170° C.

By proceeding analogously the following compounds were prepared:

4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(4-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthan-7-carboxylicacid, methyl ester;

4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(4-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(4-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2,5-dimethyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthan-7-carboxylicacid, methyl ester;

4-(2,3-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2,5-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(4-fluoro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(3,4,5-trimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(2-thenylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid,methyl ester;

4-[(3-pyridyl)-methylene]-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-[(2-pyridyl)-methylene]-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester;

4-(4-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester; and

4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, methyl ester.

EXAMPLE 9

4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid,methyl ester (1.2 g) was hydrolized by treatment with 1% KOH in 95%ethanol (19.5 ml) at reflux temperature for 15 minutes. After coolingand acidification with 37% HCl the precipitate was filtered and washedwith methanol and then with water to give 1 g of4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid,m.p. 284°-286° C., NMR (CF₃ COOD) δppm: 2.12 (m) (2H, C-2 protons), 3.13(m) (4H, C-1 and C-3 protons), 7.64 (m) (5H, phenyl protons), 8.14 (d)(1H, C-5 proton), 8.43 (bs) (1H, ═CH--), 8.88 (dd) (1H, C-6 proton),9.38 (d) (1H, C-8 proton).

By proceeding analogously the following compounds were prepared:

4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, m.p. 290°-292° C.;

4-(3-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(4-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(3-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(4-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(4-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2,5-dimethyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2,3-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2,5-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(4-fluoro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(3-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(3,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(3,4,5-trimethoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(2-thenylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid;

4-[(3-pyridyl)-methylene]-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-[(2-pyridyl)-methylene]-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid;

4-(4-chloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid; and

4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid.

EXAMPLE 10

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid (1.5 g) was reacted with thionyl chloride (10 ml) in dioxane (80ml) at the reflux temperature for 4 hours, then the mixture wasevaporated in vacuo to dryness.

The residue was dissolved in dioxane (60 ml) and reacted with2-(diethylamino)-ethanol (1.5 g) at room temperature for 20 hours. Afterconcentration in vacuo to a small volume, the residue was diluted withice water and extracted with ethyl acetate after alkalinization with Na₂CO₃. The organic solution was evaporated in vacuo to dryness:crystallization of the residue from CH₂ Cl₂ -isopropyl ether gave 0.8 gof3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester, m.p. 119°-120° C.

By proceeding analogously the following compounds were prepared:

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(dimethylamino)-ethyl ester;

3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(dimethylamino)-ethyl ester;

3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(dieethylamino)-ethyl ester;

3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7carboxylicacid, 2-(diethylamino)-ethyl ester;

4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(dimethylamino)-ethyl ester;

3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester;

3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, 2-(diethylamino)-ethyl ester; and

4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid,2-(diethylamino)-ethyl ester.

EXAMPLE 11

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid (2.4 g) was reacted with thionyl chloride (14 ml) in dioxane (110ml) at the reflux temperature for 4 hours, then the mixture wasevaporated in vacuo to dryness.

The residue was dissolved in dioxane (85 ml) and reacted with excess ofammonia solution in dioxane (20 ml) under stirring at room temperaturefor 30 minutes. After concentration in vacuo, the residue was dilutedwith ice water and the precipitate was filtered and washed with wateruntil neutral. After desiccation in vacuo, the obtained3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxamidem.p. 293°-295° C. (2.1 g) was treated with p-toluenesulphonyl chloride(3.8 g) in pyridine (4 ml) and dimethylformamide (15 ml) at 80° C. for 6hours. After cooling and dilution with ice water, the precipitate wasfiltered and washed with water until neutral: crystallization from CH₂Cl₂ -isopropyl ether gave7-cyano-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-onem.p. 260°-262° C. (1.6 g), which was reacted with sodium azide (3.3 g)and ammonium chloride (2.7 g) in dimethylformamide (15 ml) at 90° C. for4 hours.

After cooling, dilution with ice water and acidification with 37% HCl,the precipitate was filtered and washed with water until neutral.Crystallization from CHCl₃ -ethanol gave 1 g of3-(2-methyl-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 300°-307° C. dec., NMR (CDCl₃ +CF₃ COOD) δppm: 2.57 (s) (3H, CH₃),3.30 (m) (4H, C-1 and C-2 protons), 7.37 (m) and 7.64 (m) (3H and 1H,phenyl protons), 7.99 (t) (1H, ═CH--), 8.11 (d) (1H, C-5 proton), 8.68(dd) (1H, C-6 proton), 9.16 (d) (1H, C-8 proton).

By proceeding analogously the following compounds were prepared:

3-(3-methyl-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-methyl-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-methoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-methoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-ethoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,3-dimethoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,5-dimethoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,6-dichloro-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-chloro-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,5-dimethyl-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-ethoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methoxy-3-ethoxy-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;and

3-(4-fluoro-benzylidene)-7-(1H-tetrazol-5-yl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one.

EXAMPLE 12

6-N-acetylamino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 275°-282° C. dec. (9 g), was reacted with benzaldehyde (5.9 g) inmethanol (270 ml) in the presence of sodium methylate (4 g) understirring at 60° C. for 15 hours. After cooling the precipitate wasfiltered and washed with methanol and then with water until neutral: itwas found to be a mixture of the compounds6-N-acetylamino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 243°-245° C., and6-N-acetylamino-3-(α-hydroxy-benzyl)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 282°-283° C., which were identified on a sample after separationover a flash column using chloroform:ethanol=93:7 as eluent. The mixture(8.5 g), without separation of the components, was suspended understirring in 37% HCl (85 ml) and heated at 80° C. for 2 hours. Aftercooling, dilution with ice water and neutralization with NaOH, theprecipitate was filtered and washed with water: crystallization fromchloroform-methanol gave 5.9 g of6-amino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 282°-285° C., NMR (DMSO d6) δppm: 2.6-3.1 (m) (4H, C-1 and C-2protons), 6.28 (bs), (2H, --NH₂), 6.62 (m) (2H, C-5 and C-7 protons),6.99 (bs) (1H, ═CH--), 7.2-7.7 (m) (5H, phenyl protons), 7.71 (d) (1H,C-8 proton).

By proceeding analogously the following compounds were prepared:

7-amino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 245°-252° C. dec.;

7-amino-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-amino-3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2-thenylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(4-carboxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-amino-3-(4-carboxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-amino-3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;and

6-amino-3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one.

EXAMPLE 13

6-amino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one(3.8 g), was reacted with ethyl oxalyl chloride (3.6 g) indimethylacetamide (80 ml) in the presence of pyridine (3.8 ml) understirring at room temperature for 2 hours. The reaction mixture was thendiluted with ice water and the precipitate was filtered and washed withwater: crystallization from CH₂ Cl₂ -isopropyl ether gave 3.5 g ofN-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-oxoaceticacid, ethyl ester, m.p. 234°-235° C., which, was hydrolized by treatmentwith 1% KOH in 95% ethanol (175 ml) at room temperature for 30 minutes.After dilution with acetone (175 ml) the precipitate,N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-oxoaceticacid, potassium salt, was filtered and dissolved in formic acid:dilution with water gave a precipitate which was filtered and washedwith water until neutral. Crystallization from dimethylformamide-ethanolgave 2.9 g ofN-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-oxoaceticacid, m.p. 253°-256° C., NMR (DMSO d₆) δppm: 2.80 (m) (2H, C-1 protons),3.15 (m) (2H, C-2 protons), 7.23 (bs) (1H, ═C--), 7.30-7.55 (m) (3H) and7.65 (bd) (2H) (phenyl protons), 7.78 (dd) (1H, C-7 proton), 8.03 (d)(1H, C-8 proton), 8.32 (d) (1H, C-5 proton), 11.20 (bs) (1H, --NH--).

By proceeding analogously the following compounds were prepared:

N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(3,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl)-amino-oxoaceticacid, ethyl ester; m.p. 263°-266° C.;

N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxocyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl]-amino-oxoaceticacid, ethyl ester;

N-[3-(2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid, ethyl ester;

N-{3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl}-amino-oxoaceticacid, ethyl ester;

N-{3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl}-amino-oxoaceticacid, ethyl ester;

N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3,4-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3,4,5-trimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3,4-methylenedioxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl)-amino-oxoaceticacid, m.p. 300°-305° C.;

N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl]-amino-oxoaceticacid;

N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl]-amino-oxoaceticacid;

N-[3-(2-thenylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-{3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl}-amino-oxoaceticacid;

N-{3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl}-amino-oxoaceticacid;

3-benzylidene-6-N-methoxycarbonyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-ethoxycarbonyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-N-methoxycarbonyl-amino-1,2,3,9-terahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-N-ethoxycarbonyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

N-[3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6yl]-amino-oxoaceticacid;

N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,4,-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(3-methoxy-2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;

N-[3-(2,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid; and

N-[3-(3,4-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[a][1]benzopyran-6-yl]-amino-oxoaceticacid.

EXAMPLE 14

By proceeding according to Example 13, using suitable acyl chlorides,the following compounds were prepared:

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl-aceticacid, ethyl ester;

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl-aceticacid;

3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-propanoicacid, methyl ester;

3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-propanoicacid;

(E)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid, ethyl ester, m.p. 291°-293° C.;

(E)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid, m.p. 340°-350° C. dec.;

(E)-3-{N-[3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl)-aminocarbonyl]-2-propenoicacid;

3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-benzoicacid, m.p. 370°-373° C.;

4-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-benzoicacid;

(E)-3-{N-[3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2propenoicacid;

(E)-3-{N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(E)-3-{N-[3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid; and

(E)-3-{N-[3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid.

EXAMPLE 15

6-amino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one(3 g) was reacted with maleic anhydride (4.55 g) in dioxane (90 ml)under stirring at the reflux temperature for 14 hours.

After cooling the precipitate was filtered and washed withtetrahydrofuran and then with water: crystallization fromchloroform-ethanol gave 2.5 g of(Z)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid, m.p. 230° C. dec.

By proceeding analogously the following compounds were prepared:

(Z)-3-{N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl)-aminocarbonyl]-2-propenoicacid;

2-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-benzoicacid, m.p. 250° C. dec.;

2-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yl)-aminocarbonyl]-benzoicacid;

(Z)-3-{N-[3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid;

(Z)-3-{N-[3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]aminocarbonyl}-2-propenoicacid; and

(Z)-3-{N-[3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-aminocarbonyl}-2-propenoicacid.

EXAMPLE 16

By proceeding according to Example 12, starting from6-N-acetylamino-1,2,3,4-tetrahydro-9H-xanthen-9-one, the followingcompounds were prepared:

6-N-acetylamino-4-benzylidene-1,2,3,4-tetrahydro-9H-xanthen-9-one;

7-N-acetylamino-4-benzylidene-1,2,3,4-tetrahydro-9H-xanthen-9-one;

6-amino-4-benzylidene-1,2,3,4-tetrahydro-9H-xanthen-9-one;

7-amino-4-benzylidene-1,2,3,4-tetrahydro-9H-xanthen-9-one;

6-amino-4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9H-xanthen-9-one;

6-amino-4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9H-xanthen-9-one;

7-amino-4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9H-xanthen-9-one;

7-amino-4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9H-xanthen-9-one;and

6-amino-4-(4-carboxy-benzylidene)-1,2,3,4-tetrahydro-9H-xanthen-9-one.

EXAMPLE 17

By proceeding according to Example 13, starting from suitableamino-4-benzylidene-1,2,3,4-tetrahydro-9H-xanthen-9-ones, the followingcompounds were prepared:

N-(4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-6-yl)-amino-oxoaceticacid;

N-[4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-6-yl]-amino-oxoaceticacid;

N-[4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-6-yl]-amino-oxoaceticacid;

N-(4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-yl)-amino-oxoaceticacid;

N-[4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-yl]-amino-oxoaceticacid;

N-[4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-yl]-amino-oxoaceticacid;

4-benzylidene-6-N-ethoxycarbonyl-amino-1,2,3,4-tetrahydro-9H-xanthen-9-one;and

4-benzylidene-7-N-ethoxycarbonyl-amino-1,2,3,4-tetrahydro-9H-xanthen-9-one.

EXAMPLE 18

6-amino-3-benzylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one(2.3 g) was reacted with chloroacetyl chloride (1.35 g) indimethylacetamide (100 ml) in the presence of pyridine (1.9 ml) at roomtemperature for 3 hours.

The reaction mixture was diluted with ice water and the precipitate wasfiltered and washed with water to give3-benzylidene-6-N-chloroacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 308°-312° C. (2.3 g), which was reacted with morpholine (0.63 g) indimethylacetamide (90 ml) in the presence of anhydrous potassiumcarbonate (1 g) under stirring at 60° C. for 4 hours. After cooling theprecipitate was filtered and washed with water: crystallization fromchloroform-ethanol gave 1.3 g of3-benzylidene-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 163°-167° C. dec.

By proceeding analogously the following compounds were prepared:

3-(2-methyl-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methoxy-3-ethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one

3-(4-ethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,3-dimethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-piperidinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methyl-benzylidene)-6-N-piperidinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-methoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-[(4-methyl-piperazin-1-yl)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methyl-benzylidene)-6-N-[(4-methyl-piperazin-1-yl)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methoxy-benzylidene)-6-N-[(4-methyl-piperazin-1-yl)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-[(pyrrolidin-1-yl)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-methyl-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;3-benzylidene-6-N-[(N,N-diethylamino)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-[(N-isopropylamino)-acetyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-flfuoro-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-chloro-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-chloro-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2,6-dichloro-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-methyl-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-chloro-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-ethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(3-ethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-methoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;and

3-(2,5-dimethoxy-benzylidene)-6-N-morpholinoacetyl-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one.

EXAMPLE 19

By proceeding according to Examples 1, 5 and 6, starting from suitable1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-ones or1,2,3,4-tetrahydro-9H-xanthen-9-ones, the following compounds wereprepared:

3-benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 320°-325° C. dec.;

3-benzylidene-7-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 321°-322° C.;

6-hydroxy-3-thenylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-hydroxy-3-thenylidene-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-hydroxy-3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-hydroxy-3-[(2-pyridyl)-methylene]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-hydroxy-3-[(3-pyridyl)-methyl]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-hydroxy-3-[(3-pyridyl)-methylene]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

4-benzylidene-6-hydroxy-1,2,3,4-tetrahydro-9H-xanthen-9-one;

4-benzylidene-7-hydroxy-1,2,3,4-tetrahydro-9H-xanthen-9-one;

6-hydroxy-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

6-hydroxy-3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-hydroxy-3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

7-hydroxy-3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-methoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-methoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(4-carboxy-benzylidene)-6-hydroxy-1,2,3,9-tetrahydrocyclopenta[b][1]benzopyran-9-one;

3-(4-carboxy-benzylidene)-7-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-chloro-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-chloro-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-methyl-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-methyl-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

4-benzylidene-6-hydroxy-1,2,3,4-tetrahydro-9H-xanthen-9-one; and

4-benzylidene-7-hydroxy-1,2,3,4-tetrahydro-9H-xanthen-9-one.

EXAMPLE 20

By proceeding according to Examples 13 and 15 starting fromhydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one, thefollowing compounds were prepared:

(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-oxoaceticacid, ethyl ester;

(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yloxy)-oxoaceticacid, ethyl ester;

3-[(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-carbonyl]-propanoicacid;

3-[(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yloxy)-carbonyl]-propanoicacid;

(Z)-3-[(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-carbonyl]-2-propenoicacid; and

(Z)-3-[(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-yloxy)-carbonyl]-2-propenoicacid.

EXAMPLE 21

By proceeding according to Example 18 starting fromhydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one, thefollowing compounds were prepared:

3-benzylidene-6-morpholinoacetoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-morpholinoacetoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 204°-206° C.;

3-benzylidene-6-piperidinoacetoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-piperidinoacetoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-[(4-methyl-piperazin-1-yl)-acetoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-[(4-methyl-piperazin-1-yl)-acetoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;and

3-benzylidene-7-chloroacetoxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 190°-204° C.(dec).

EXAMPLE 22

3-(4-nitro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester (3.8 g), was reacted with SnCl₂.2H₂ O (11.5 g) inacetic acid (130 ml) and 37% HCl (26.5 ml) under stirring at 60° C. for3 hours: after cooling the precipitate was filtered and washed with 2NHCl and water finely dispersed in 2N NaOH. The precipitate was filteredand washed with water until neutral to give3-(4-amino-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, methyl ester m.p. 265°-268° C. (2.9 g), which was treated with 37%HCl (60 ml) in acetic acid (120 ml) under stirring at 100° C. for 4hours. After cooling the precipitate was filtered and then suspendedunder stirring in water containing Na₂ HPO₄ : the precipitate wasfiltered and washed with water to give 2.1 g of3-(4-amino-benzylidene)-1,2,3,9tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, m.p. 360° C. dec., NMR (DMSO d₆) δppm: 2.90 (m) (4H, C-1 and C-2protons), 3.30 (bs) (2H, NH₂), 6.64 (d) (2H, C-3 and C-5 phenylprotons), 7.01 (bs) (1H═CH--), 7.31 (d) (2H, C-2 and C-6 phenyl protons,7.69 (d) (1H, C-5 proton), 8.19 (dd) (1H, C-6 proton), 8.59 (d) (1H, C-8proton).

EXAMPLE 23

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid (2 g) was dissolved in the stoichiometric amount of 4N NaOH byheating at 80° C. After concentration in vacuo about to dryness anddilution of the residue with acetone (100 ml), the precipitate wasfiltered and washed with acetone: 1.85 g of3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt, m.p. >300° C., were obtained.

By proceeding analogously the following compounds were obtained:

3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt;

3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt;

3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt;

3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt;

3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt; and

3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, sodium salt.

EXAMPLE 24

3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one(1.5 g) was reacted with ethyl 2-bromo-acetate (1.67 g) indimethylformamide (60 ml), in the presence of anhydrous K₂ CO₃ (1.38 g),under stirring at room temperature for 3 hours. The reaction mixture wasdiluted with ice water containing NaH₂ PO₄ and the precipitated productwas filtered and washed with water: crystallization from CH₂ Cl₂/methanol gave(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)aceticacid, ethyl ester, m.p. 152°-154° C. (1.75 g), which was dissolved indimethylformamide (22 ml) and treated with 2N NaOH (11.5 ml) at roomtemperature for 2 hours. The reaction mixture was acidified with 2N HCland then diluted with ice water: the precipitated product was filteredand washed with water until neutral. Crystallization from CHCl₃ /ethanolgave 1.4 g of (3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-acetic acid, m.p. 277°-279° C.

By proceeding analogously the following compounds were prepared:

[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

3-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-propanoicacid;

[3-(3-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(4-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-aceticacid;

3-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy]-propanoicacid;

N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-aceticacid;

N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-aceticacid;

3-N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-propanoicacid; and

3-N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-propanoicacid.

EXAMPLE 25

3-Benzylidene-6-hydroxy-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one(1.2 g) was reacted with 4-(2-chloro-ethyl)-morpholine (1.15 g) indimethylformamide (50 ml), in the presence of anhydrous K₂ CO₃ (1.7 g),under stirring for 4 hours at room temperature and then for 1 hour at70° C. The reaction mixture was diluted with ice water containing NaH₂PO₄ and the precipitated product was filtered and washed with water.Crystallization from CH₂ Cl₂ /isopropyl alcohol gave 0.9 g of3-benzylidene-6-(2-morpholino-ethoxy)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one,m.p. 167°-169° C.

By proceeding analogously the following compounds were prepared:

3-(2-methyl-benzylidene)-6-(2-morpholino-ethoxy)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-(2-piperidino-ethoxy)-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-[2-(pyrrolidin-1-yl)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-(2-morpholino-ethyl)-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methyl-benzylidene)-6-N-(2-morpholino-ethyl)-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-N-(2-piperidino-ethyl)-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;and

3-benzylidene-6-N-[2-(pyrrolidin-1-yl)-ethyl]-amino-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one.

3-benzylidene-7-[2-(N,N-dimethyl-amino)-ethoxy]-1,2,3,4-tetrahydro-9H-xanthen-9-one;

3-benzylidene-6-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methyl-benzylidene)-6-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-6-[2-(N,N-dimethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-(2-methyl-benzylidene)-7-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

3-benzylidene-7-[2-(N,N-dimethyl-amino)-ethoxy]-1,2,3,9-tetrahydro-cyclopenta[b][1]benzopyran-9-one;

4-benzylidene-6-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,4-tetrahydro-9H-xanthen-9-one;

4-benzylidene-7-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,4-tetrahydro-9H-xanthen-9-one;and

4-(2-methyl-benzylidene)-7-[2-(N,N-diethyl-amino)-ethoxy]-1,2,3,4-tetrahydro-9H-xanthen-9-one.

EXAMPLE 26

Tablets, each weighing 200 mg and containing 100 mg of the activesubstances were manufactured as follows: Compositions (for 10,000tablets)

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid: 1000 g

Lactose: 710 g

Corn starch: 237.5 g

Talc powder: 37.5 g

Magnesium stearate: 15 g

3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid, lactose and a half of the corn starch were mixed; the mixture wasthen forced through a sieve of 0.5 mm openings. Corn starch (18 g) wassuspended in warm water (180 ml). The resulting paste was used togranulate the powder. The granules were dried, comminuted on a sievesize 1.4 mm, then the remaining quantity of starch, talc and magnesiumstearate was added, carefully mixed and processed into tablets usingpunches of 8 mm diameter.

We claim:
 1. A compound of formula (I) ##STR24## wherein R₁ is amino,hydroxy, carboxy, C₁ -C₄ alkoxycarbonyl unsubstituted or substituted bydi(C₁ -C₄)alkylamino, --NHCOCOOR, --NHCOCH═CH--COOR, wherein R ishydrogen or C₁ -C₄ alkyl, --NHCO(CH₂)_(p) --COOR or --O--(CH₂)_(p)--COOR, wherein p is 1, 2 or 3 and R is as defined above;each of R₈ andR₉ independently is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,di(C₁ -C₄) alkylamino or R₈ and R₉, being adjacent, taken together forma methylenedioxy group; or a pharmaceutically acceptable salt thereof.2. A compound of formula (I) ##STR25## wherein R₁ is amino, hydroxy,carboxy, or C₁ -C₄ alkoxy-carbonyl unsubstituted or substituted by di(C₁-C₄)alkylamino;each of R₈ and R₉ independently is hydrogen, halogen, C₁-C₄ alkyl, C₁ -C₄ alkoxy, or di(C₁ -C₄)alkylamino; or a pharmaceuticallyacceptable salt thereof.
 3. A compound selected from the groupconsistingof:3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(3-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2,5-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(3-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxylicacid;3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-7-carboxlicacid;N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-amino-oxoaceticacid;N-[3-(2-methyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(2-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(4-chloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(4-fluoro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(4-ethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(4-methoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(2,5-dimethyl-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(2,3-dimethoxy-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(2,6-dichloro-benzylidene)-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;N-[3-(3-chloro-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl]-amino-oxoaceticacid;(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yloxy)-aceticacid;(E)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid;(Z)-3-[N-(3-benzylidene-1,2,3,9-tetrahydro-9-oxo-cyclopenta[b][1]benzopyran-6-yl)-aminocarbonyl]-2-propenoicacid;or a pharmaceutically acceptable salt thereof.
 4. An anti-allerycomposition comprising an anti-allergic effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 5. A method ofproducing an anti-allergic effect in a patient in need of such affect,said method comprising administering to said patient an anti-allergiceffective amount of a compound of the formula: ##STR26## wherein n is 1or 2;R₁ is(a) hydrogen, halogen or C₁ -C₆ alkyl; (b) cyano,aminocarbonyl, carboxy or a C₁ -C₆ alkoxycarbonyl group unsubstituted orsubstituted by a di(C₁ -C₆)alkylamino group; (c) nitro, amino; (d) a##STR27## group, wherein R₃ is hydrogen or C₁ -C₆ alkyl and R₄ is:(a')formyl, C₂ -C₆ alkanoyl or C₁ -C₆ alkyl, wherein the alkyl isunsubstituted or substituted by one or two substituents chosen fromhydroxy and phenyl; (b') a--(CO)_(m) --A--R₅ group, wherein m is zero or1; A completes a single bond, or is a phenylene moiety, or it is abranched or straight C₁ -C₆ alkylene or C₂ -C₆ alkenylene chain and R₅is:(a") carboxy or C₁ -C₆ alkoxycarbonyl, unsubstituted or substitutedby a di-(C₁ -C₆)alkyl-amino group; or (b") halomethyl or ##STR28##wherein each of R₆ and R₇ is independently hydrogen or C₁ -C₆ alkyl (e)hydroxy or a --OR₄ group, wherein R₄ is as defined above; R₂ is a groupof the formula ##STR29## wherein each of R₈, R₉ and R₁₀ is independentlyhydrogen; halogen; C₁ -C₆ alkyl; hydroxy; C₁ -C₆ alkoxy; C₃ -C₄alkenyloxy; formyloxy; C₂ -C₆ alkanoyloxy; carboxy; C₁ -C₆alkoxycarbonyl; nitro; or a group ##STR30## wherein each of R₁₁ and R₁₂independently represents hydrogen, C₁ -C₆ alkyl, formyl or C₂ -C₆alkanoyl; or any two adjacent R₈, R₉ and R₁₀ groups, taken together,form a C₁ -C₃ alkylenedioxy group, or a pharmaceutically acceptable saltthereof, and wherein, when n is 1 and, at the same time, R₂ isunsubstituted phenyl, R₁ is other then hydrogen.